The Women's Health Initiative trial (WHI), which employed conjugated equine estrogens alone (Premarin) or in conjunction with MPA (Prempro) has turned women's health at menopause into a minefield. The combined hormone arm was ended prematurely due to increased incidence of breast cancer. Increased risk of artherosclerosis, stroke and cognitive decline was also present in both arms relative to placebo. While the WHI trial revealed the risks associated with Prempro in post-menopausal women, it generated considerable controversy in the field because it was interpreted as an indictment of post-menopausal hormone replacement, when in fact, it did not study hormone replacement, which would have required use of the natural hormones, estradiol (E) and progesterone. The actions of the natural hormones are significantly different from those of Premarin or Prempro. In addition, WHI administered the synthetic hormones a decade or more after menopause, raising the question of whether there is an optimal time frame for hormone therapy. There have been follow up studies, which have used natural hormones and shown that indeed, they need to be administered at perimenopause, but the endpoints were limited to one or two systems. We hypothesize that estrogen (E) replacement will be beneficial when started immediately after ovariectomy/hysterectomy (Ovx), but delayed treatment will have no beneficial, or even adverse, effects on many of the systems under study. We propose to establish a postmenopausal monkey resource with aged Ovx rhesus monkeys on a Western diet and treated with placebo, immediate-E or delayed-E replacement. We will obtain longitudinal assessments of social behavior, activity, temperature, cognitive function, brain structure, immune function, fat accumulation, glucose metabolism and bone density. We will obtain postmortem assessments of coronary arteries, breast tissue, fat insulin sensitivity, and determine the cellular and molecular function of multiple neural systems. PUBLIC HEALTH RELEVANCE (provided by applicant): This resource will be an outstanding model of late middle aged women after complete hysterectomy, which mimics menopause in significant ways. The loss of ovarian steroids at menopause impacts many physiological systems in women, but the formulation and timing of hormone therapy is controversial. Our project will provide critical information to all on the optimal and safe use of estrogen therapy.